As the title reflects, the emphasis is on basic mechanisms and effects of chronic intestinal inflammation. Many of the studies will be done in two newly developed experimental mouse models of colitis. This makes available a rich array of techniques and reagents available only in the mouse and engages established investigators who are new to the area of IBD, including investigators with great expertise in the area of mucosal immunology. The Program Project will be headed by Dr. Charles Elson and will consist of four projects and two sub-cores. These projects will investigate the colon autoantigens recognized by T cells during colitis and the assortment of T cell receptors used to recognize those antigens (C.O. ELson, P.I.), the function of the secretory immune system in the setting of chronic inflammation, including mucosal immunization, tolerance, isotype regulation (J.R. McGhee, P.I.), the role cytokines play in acute and chronic colitis (K.W. Beagley, P.I.), and the mechanisms involved in tissue matrix damage and repair in Crohn's diseases and ulcerative colitis (S. Gay, P.I.). These projects will be supported by an Administrative Core which will provide administrative and fiscal support and coordination, and an Animal Model Core which will centralize the production of mice with experimental colitis and maintain strict quality control. An important sub-core within the Animal Model Core is a developmental project to be located at Jackson Laboratories in Bar Harbor, Maine to develop new mouse models of inflammatory bowel disease by selective breeding of mutants and by transgenic technology, and further, to map the number and location of the genes involved in the former. The results of these studies will be compared to existing data on human IBD and will serve to focus and enhance future studies in man.